AI-Powered Drug Discovery Breakthrough: PharmaEngine Submits IND for Next-Gen PRMT5 Inhibitor PE-0260, Enabled by XtalPi

Another New Achievement in AI-Driven Drug Discovery

XtalPi AI Drug Discovery Platform EmpowersPharmaEngine Inc.（PharmaEngine, Inc.) developed PE-0260, an orally available, blood-brain barrier penetrable, highly selective PRMT5 (Protein Arginine Methyltransferase 5) inhibitor that binds to PRMT5 through an MTA cooperative binding mode, forming a stable ternary complex. This mechanism achieves selective inhibition of PRMT5, specifically targeting MTAP-deficient tumor cells while having no effect on normal MTAP wild-type cells. Compared with first-generation non-selective PRMT5 inhibitors, this targeted binding strategy significantly enhances the therapeutic window. Currently,PharmaEngineCompletedPE-0260 IND submission preparation is underway, with plans to enter the clinical development stage in the second half of 2025.

Recently,PharmaEngine Inc. Discloses Core Preclinical R&D Data of Its Project for the First Time at the 2025 AACR Annual Meeting; This Article Will Provide an In-Depth Analysis of the Research Process and Outstanding Achievements.

Project Background: Targeting MTAP

Unmet Clinical Needs in Deletion-Type Tumors

PRMT5 Has Been Identified as a Synthetic Lethal Target in Cancers with Homozygous Deletion of the Methylthioadenosine Phosphorylase (MTAP) Gene. MTAP Plays a Central Role in the Methionine Salvage Pathway, and Its Loss Leads to the Accumulation of Methylthioadenosine (MTA), Which Partially Inhibits PRMT5 Activity. In MTAP-Deficient Tumor Cells, the Expression and Activity of PRMT5 Become Essential for Cell Proliferation, Making PRMT5 an Attractive Synthetic Lethal Target for the Treatment of Such Cancers.^[1-3]。

The homozygous deletion of MTAP occurs in 10% to 15% of human cancers, with particularly significant deletion frequencies in non-small cell lung cancer (NSCLC), mesothelioma, pancreatic cancer, GBM, head and neck cancer, esophageal cancer, and bladder cancer. Existing therapies have limited efficacy. Traditional PRMT5 inhibitors lack selectivity, making the development of highly effective and low-toxicity new drugs urgently needed.

Figure 1

A. The accumulation of MTA in MTAP-deficient cells reduces PRMT5 activity and decreases SDMA modification of PRMT5 substrates.

B. Frequency of MTAP Deletion in Human Cancers (Data from TCGA Pan-Cancer Atlas, *Cortes-Ciriano et al., Cancer Discov. 2023).

C. PE-0260 acts on PRMT5 through an MTA cooperative binding mechanism, achieving stronger inhibitory selectivity in MTAP-deficient cancer cells.

Discovery of PE-0260

The competition for this target is currently extremely fierce, making the novelty of molecular design a key factor.In this project,XtalPi has demonstrated exceptional strength in the field of molecular design. Relying on XtalPi's self-developed artificial intelligence drug discovery platform ID4Inno^TM, by integrating the three core technology modulesBlockAs well as PharmaEngine Inc. and XtalPi's extensive experience in drug development and project management.AchieveInnovation Breakthrough:

Specifically, in optimizingXFEPDuring the process of computational modeling, no co-crystal structures of the relevant molecules were disclosed in the early stage of the project. XtalPi performed modeling through its computational platform and utilized Xpose for conformational optimization, successfully constructing a usable complex base model. Notably, the initial FEP calculations showed a correlation coefficient between the predicted values and experimental data.R²Only for0.44, By implementing structured data augmentation strategies and multi-objective optimization algorithms, and combining the experience of XtalPi's computational experts, systematic optimization was performed on key parameters (such as solvents, critical amino acid conformations, force fields, and small molecule electronic properties), ultimately achieving a significant improvement in model prediction accuracy.R² increased to 0.71`, thereby effectively ensuring the benchmark for subsequent activity screening of the synthesized molecular library.`

InMolecular DesignIn terms of, XtalPi leverages its self-developedXMolGen AI Molecular Generation Platform, Efficiently Exploring Vast Chemical Space, Successfully GeneratedMillion-levelThe new molecular library. Subsequently, through molecular docking scoring and drug-like property filtering, carefully selected...5000Multiple compounds. Immediately following, utilizing XtalPi's physical computational models and robustXFFThe computing power platform conducts computational evaluations of these compounds. Combined with the extensive experience of the R&D teams from both sides, further recommendations are made for approximately 300candidate molecules. With the help of XtalPi's automated synthesis platform, the synthesis of these candidate molecules was quickly completed. Ultimately, more than10 CategoriesA series of compounds with novel scaffolds. Among them,Four lead compound series stood out particularly., whose representative molecules not onlyNovel Structure, compared with the publicly disclosed clinical compounds inSignificant differences exist in structure.(As shown in Figure 2C), it also hasHigh Activity and High SelectivityTheFeatures.

Figure 2

A. PharmaEngine Inc.FirstGuide MoleculesCryo-EM structure of the PRMT5-MTA complex.

B. Comparison of ddG Values for Lead Compounds Calculated by Free Energy Perturbation (FEP) and Experimental ddG Values (Converted from Anti-Proliferative Cell Assay IC50 Values) Across Four Different Scaffold Compound Series.

C. PEI Analysis of Structural Similarity Between Lead Compounds and Clinically Staged PRMT5-MTA Inhibitors with Disclosed Structures (References 4-6).

Structure determines properties. Representative molecules from the four different Lead frameworks exhibit significant advantages in activity, metabolic stability, and pharmacokinetic properties. Among them, PE-0260 stands out with the most comprehensive characteristics, specifically:

Compared with other drugs in the clinical stage (MRTX1719, AMG193, TNG462),PE-0260 not only features a novel structure but also demonstrates best-in-class comprehensive properties, showing further development potential.

Table 1

Comparison of In Vitro ADME Properties and Mouse PK Properties of PEI Lead Compounds with Other MTA Synergistic PRMT5 Inhibitors in Clinical Stages.

PE-0260 Excellent Preclinical Data

Cell proliferation selectivity assays conducted in HCT116 MTAP-deficient and wild-type cell lines demonstrated that PE-0260 exhibits higher selectivity (> 200-fold, Fig. 3A) compared to other MTA-cooperative PRMT5 inhibitors currently in clinical stages. PE-260 showed the largest ratio of HCT116 MTAP wild-type IC50 to knockout IC80, indicating a broader therapeutic window in vivo (Fig. 3B).

Figure 3

A. Comparison of 10-day CTG cell viability results in HCT116 MTAP-deficient and wild-type cell lines.

B. Comparison of IC50 in HCT116 MTAP wild-type cell lines and IC80 in deletion-type cell lines for PE-0260 and three clinical-stage compounds.

In the preliminary screening test for cell proliferation activity in MTAP-deleted pan-cancer, PE-0260 showed stronger inhibitory activity than AMG193 (Figure 4A). In a larger-scale tumor cell line screening, it demonstrated potent tumor suppression activity against various MTAP-deleted tumor cell lines while maintaining good selectivity for MTAP wild-type tumor cell lines (Figure 4B).

Figure 4

A. Five-day cell proliferation activity assay in MTAP-deficient tumor cell lines, head-to-head data comparison between PE-0260 and AMG193.

B. PE-0260 inhibitory activity on cell proliferation of various tumor type cell lines over 10 days; solid dots represent MTAP-deficient cell lines, and hollow dots represent MTAP wild-type cell lines.

PE-0260's excellent in vitro activity and PK properties can translate into superior in vivo efficacy. In the MTAP-deficient LU99 CDX mouse efficacy model, PE-0260 can inhibit tumor growth in a dose-dependent manner. At a low dose of 10 mg/kg, PE-0260 significantly inhibits tumor growth, outperforming MRTX1719. At 25 mg/kg, once-daily dosing for 21 days can lead to tumor regression, with tumor volume continuing to decrease 14 days after cessation of treatment (Figure 5A). Representative molecules from three other Lead series also demonstrated excellent anti-tumor activity in the LU99 in vivo efficacy model (Figure 5B).

Figure 5

A. Anti-tumor activity of PE-0260 and MRTX1719 in the LU99 CDX mouse model.

B. Anti-tumor activity of other PEI lead compounds in the LU99 CDX mouse model. Tumor regression is defined as a reduction in tumor volume of more than 30% from the initial value.

In the MTAP-deficient Mia Paca-2 CDX model, 50 mg/kg of AMG193 only partially inhibited tumor growth. Compared with the same dose of AMG 193, PE-0260 demonstrated dose-dependent antitumor activity and more significant tumor growth inhibition (Figure 6A). In terms of intratumoral PD biomarker SDMA levels, the PE-0260 treatment group showed a dose-dependent reduction in SDMA levels, with less experimental data variation (Figure 6B).

Figure 6

A. Anti-tumor activity of PE-0260 and AMG193 in the Mia Paca-2 CDX model.

B. Results of SDMA content detection in tumor samples collected 4 hours after the last dose by Western blot.

Potential Differentiation Advantages:

Excellent Brain Permeability and Combination Potential

In GBM, the proportion of MTAP deletion is as high as 40%, and these tumor patients do not have good treatment outcomes. Both MRTX1719 and TNG462 have poor brain permeability, making them difficult to use for brain tumor treatment. PE-0260 exhibits excellent brain permeability. In the LN-18 mouse orthotopic model, PE-0260 demonstrated dose-dependent antitumor activity and effectively inhibited tumor growth. At a dose of 25 mg/kg once daily (QD), the tumor signal remained at its lowest level for up to 7 days after the final dosing (Figure 7A). Bioluminescence intensity (BLI) imaging showed that on day 23, BLI was significantly reduced in 7 out of 8 animals; two complete responses were confirmed at the end of the study (Figure 7B).

Figure 7

A. Anti-tumor activity of PE-0260 in the LN-18 glioblastoma (GBM) orthotopic mouse model.

B. Bioluminescence intensity (BLI) imaging results of LN-18 orthotopic mice.

PE-0260 exhibits excellent ADME and PK properties, with no CYP inhibition issues, making it suitable for combination with drugs of different mechanisms to maximize the therapeutic potential of the target. PEP07 isPharmaEngine Inc.A clinical-stage CHK1 inhibitor with blood-brain barrier penetrability. In the Mia Paca2 CDX mouse model, the combination of PE-0260 and PEP07 demonstrated a stronger tumor suppression effect, showing a favorable synergistic effect compared to the single-agent groups. Animal body weight monitoring indicated good tolerability of the combination therapy (Figure 8A). In the LN-18 orthotopic mouse CDX model, bioluminescence signals showed that the combined application of PE-0260 and PEP07 effectively controlled tumor growth (Figure 8B).

Figure 8

A. Mia Paca2 CDX Mouse Model: Antitumor Activity of PE-0260 and PEP07 Administered as Monotherapy or in Combination.

B. LN-18 Orthotopic CDX Mouse Model: Antitumor Activity and Bioluminescence Intensity (BLI) Imaging Results of PE-0260 and PEP07 Administered as Monotherapy or Combination Therapy.

Conclusion

With the help of XtalPi's AI drug discovery platformandPharmaEngine Inc.'s extensive experience in drug development, both parties' expertsDeep collaboration, successfully developing the breakthrough therapeutic potential PRMT5 inhibitor PE-0260. Both teams utilized AI and computational chemistry.Driven by a rational drug design strategy, through the exploration of a broader chemical space and an AI-assisted molecular evaluation system that screens for activity, selectivity, drug-likeness, developability, and other factors, PE-0260 demonstrated significant differentiated advantages after multiple rounds of iterative optimization and was nominated as the preclinical candidate compound (PCC). PE-0260 showed robust in vivo efficacy at lower doses across various animal models, especially in the mouse GBM orthotopic model. It not only exhibited promising effects as a monotherapy but also displayed broad potential for combination with other therapies.

In addition, the compound exhibits excellent selectivity in MTAP-WT cell lines, reducing the risk of drug-drug interactions (DDI), while demonstrating favorable pharmacokinetic (DMPK) properties, with the potential to become a best-in-class MTA-cooperative PRMT5 inhibitor.PharmaEngine Inc.The IND application preparation for PE-0260 has been completed and clinical research is planned to commence in the second half of 2025.

References

1. N. Stopa et al, Cell. Mol. Life Sci., 2015, 72, 2041

2. H. Kim et al, Cell Stress, 2020, 4(8), 199

3. K. J. Mavrakis et al, Science., 2016, 351(6278), 1208

4. Engstrom LD, et al, Cancer Discovery 2023, 13(11), 2412.

5. Rodon J, et al, AACR-NCI-EORTC 2023, abstract PR006

6. Cottrell K, et al, ACS Fall Meeting 2023, Abstract 3900386.

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